PROJECT SUMMARY/ABSTRACT Arterial disease is the leading cause of morbidity/mortality in Metabolic syndrome (MetS). This occurs early as evidenced by arterial dysfunction that, in turn, raises blood pressure and glucose. Health organizations recommend exercise in an intensity based manner to promote cardiovascular adaptation and prevent disease. Metformin is a common anti-diabetes medication that reduces future type 2 diabetes and CVD risk. However, the optimal exercise dose to be combined with metformin for additive effects on vascular function is unknown. Based on our preliminary work, our overall hypothesis is that metformin blunts adaptation following high intensity exercise training (HiEx) by lowering mitochondrial derived oxidative stress signaling. We further hypothesize that low intensity exercise (LoEx) training combined with metformin will promote additive effects on vascular function compared to LoEx or HiEx+metformin, and maintain/improve non-exercise physical activity patterns. In this double-blind trial, obese 30-60y MetS patients will be randomized to: 1) LoEx+placebo; 2) LoEx+metformin, 3) HiEx+placebo; or 4) HiEx+metformin for 16 weeks. We will evaluate measures of arterial stiffness (pulse wave velocity and augmentation index), and nitric oxide-mediated arterial function in conduit (flow mediated dilation), resistance (post-ischemic flow velocity) and microvascular (contrast enhanced ultrasound) vessels, before and during a euglycemic clamp pre and post intervention (AIM 1). We will also assess 24 hr blood pressure as well as determine skeletal muscle metabolic insulin resistance and glucose tolerance (AIM 2) to address clinical and experimental questions related to health care. Further, we will examine the effect of metformin on exercise adherence, non-exercise physical activity and quality of life during the 16 week intervention as well as during an 8 week ?free-living? period (Exploratory AIM 3) to improve public health physical activity recommendations when co-prescribed medication. If these hypothesis are correct, they will indicate 1) whether and how metformin should be combined with physical activity for CVD prevention, 2) provide the first indication of whether exercise intensity reduces CVD risk via multi-level vasculature function vs. metabolic insulin action, 3) provide a rational early treatment for people with MetS. Thus, identification of the optimal drug to exercise interaction will illuminate how to develop individualized exercise/metformin prescriptions to correct vascular and ameliorate metabolic insulin resistance that attenuate/prevent progression to future diabetes and the CV morbidity and mortality.